Post-transplant lymphoproliferative disorders (PTLD) contribute significantly to the morbidity and mortality of these procedures. The current application seeks to address areas of clinical and laboratory investigation identified as important in a recent international consensus document. We plan a prospective multi-center clinical trial in which PTLD patients will be uniformly classified according to clinical and pathologic characteristics. Immunosuppressive medication will be reduced followed by observation. Patients who do not completely remit will enter a phase II trial to determine the safety and efficacy of the anti- CD20 antibody, rituximab. The accompanying tissue acquisition protocol will afford standardized diagnostic evaluation to include clonality, Epstein-Barr association and laboratory investigations. Mutations in the BCL-6 gene will be assessed by a single strand conformational polymorphisms and results will be correlated with clinical response to reduced immunosuppression and rituximab. Immunohistochemical analyses to determine the histogenesis of PTLD, proliferative fraction and bcl-2 expression are planned. Epstein-Barr viral genomes in the peripheral blood will be quantified using real-time PCR and the results will be correlated with response to reduced immunosuppression, rituximab and overall outcome. In Aim 2 of this project gene expression patterns in PTLD will be evaluated using micro-array technology in conjunction with investigators in Project 5. We hypothesize that gene expression will improve our ability to predict the behavior of these heterogeneous disorders, for which routine pathologic analysis is inadequate. Differences in expression patterns may also predict response to our therapeutic interventions and provide clues to new treatments.